Frailty syndrome: an overview

Xujiao Chen, Genxiang Mao, Sean X Leng, Xujiao Chen, Genxiang Mao, Sean X Leng

Abstract

Frailty is a common and important geriatric syndrome characterized by age-associated declines in physiologic reserve and function across multiorgan systems, leading to increased vulnerability for adverse health outcomes. Two major frailty models have been described in the literature. The frailty phenotype defines frailty as a distinct clinical syndrome meeting three or more of five phenotypic criteria: weakness, slowness, low level of physical activity, self-reported exhaustion, and unintentional weight loss. The frailty index defines frailty as cumulative deficits identified in a comprehensive geriatric assessment. Significant progress has recently been made in understanding the pathogenesis of frailty. Chronic inflammation is likely a key pathophysiologic process that contributes to the frailty syndrome directly and indirectly through other intermediate physiologic systems, such as the musculoskeletal, endocrine, and hematologic systems. The complex multifactorial etiologies of frailty also include obesity and specific diseases. Major clinical applications include risk assessment and stratification. This can be applied to the elderly population in the community and in a variety of care settings. Frailty may also be useful for risk assessment in surgical patients and those with cardiovascular diseases, cancer, or human immunodeficiency virus infection, as well as for assessment of vaccine effectiveness in older adults. Currently, exercise and comprehensive geriatric interdisciplinary assessment and treatment are key interventions for frailty. As understanding of the biologic basis and complexity of frailty further improves, more effective and targeted interventional strategies and innovative geriatric-care models will likely be developed.

Keywords: IL-6; aging; frailty; inflammation; older adults.

Figures

Figure 1
Figure 1
Venn diagram of the frailty syndrome, activities of daily living (ADL) disability, and comorbidity (two or more diseases) in the Cardiovascular Health Study dataset, demonstrating frailty as a distinct geriatric syndrome with some overlap with disability and comorbidity. Fried LP, Tangen C, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56A:M1–M11, by permission of Oxford University Press. Note: *Two or more out of the following nine diseases: myocardial infarction, angina, congestive heart failure, claudication, arthritis, cancer, diabetes, hypertension, COPD.
Figure 2
Figure 2
Pathogenesis of the frailty syndrome: current understanding of potential underlying mechanisms and hypothetical modal pathways leading to frailty. Abbreviation: CMV, Cytomegalovirus.

References

    1. Fried LP, Hadley EC, Walston JD, et al. From bedside to bench: research agenda for frailty. Sci Aging Knowledge Environ. 2005;2005(31):pe24.
    1. Walston J, Hadley EC, Ferrucci L, et al. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc. 2006;54:991–1001.
    1. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet. 2013;381:752–762.
    1. Lipsitz LA. Dynamics of stability: the physiologic basis of functional health and frailty. J Gerontol A Biol Sci Med Sci. 2002;57:115–125.
    1. Fried LP, Tangen C, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56A:M1–M11.
    1. Bortz WM. The physics of frailty. J Am Geriatr Soc. 1993;41:1004–1008.
    1. Lipsitz LA, Goldberger AL. Loss of ‘complexity’ and aging. Potential applications of fractals and chaos theory to senescence. JAMA. 1992;267:1806–1809.
    1. Jones DM, Song X, Rockwood K. Operationalizing a frailty index from a standardized comprehensive geriatric assessment. J Am Geriatr Soc. 2004;52:1929–1933.
    1. Abellan van KG, Rolland Y, Bergman H, Morley JE, Kritchevsky SB, Vellas B. The I.A.N.A Task Force on frailty assessment of older people in clinical practice. J Nutr Health Aging. 2008;12:29–37.
    1. Romero-Ortuno R, Walsh CD, Lawlor BA, Kenny RA. A frailty instrument for primary care: findings from the Survey of Health, Ageing and Retirement in Europe (SHARE) BMC Geriatr. 2010;10:57.
    1. Peters LL, Boter H, Buskens E, Slaets JP. Measurement properties of the Groningen Frailty Indicator in home-dwelling and institutionalized elderly people. J Am Med Dir Assoc. 2012;13:546–551.
    1. Morley JE, Vellas B, van Kan GA, et al. Frailty consensus: a call to action. J Am Med Dir Assoc. 2013;14:392–397.
    1. Fried LP, Borhani NO, Enright P, et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol. 1991;1:263–276.
    1. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci. 2004;59:255–263.
    1. Bandeen-Roche K, Xue QL, Ferrucci L, et al. Phenotype of frailty: characterization in the women’s health and aging studies. J Gerontol A Biol Sci Med Sci. 2006;61:262–266.
    1. Santos-Eggimann B, Cuenoud P, Spagnoli J, Junod J. Prevalence of frailty in middle-aged and older community-dwelling Europeans living in 10 countries. J Gerontol A Biol Sci Med Sci. 2009;64:675–681.
    1. Alvarado BE, Zunzunegui MV, Beland F, Bamvita JM. Life course social and health conditions linked to frailty in Latin American older men and women. J Gerontol A Biol Sci Med Sci. 2008;63:1399–1406.
    1. Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A standard procedure for creating a frailty index. BMC Geriatr. 2008;8:24.
    1. Rockwood K, Mitnitski A. Frailty defined by deficit accumulation and geriatric medicine defined by frailty. Clin Geriatr Med. 2011;27:17–26.
    1. Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci. 2007;62:722–727.
    1. Fried LP, Xue QL, Cappola AR, et al. Nonlinear multisystem physiological dysregulation associated with frailty in older women: implications for etiology and treatment. J Gerontol A Biol Sci Med Sci. 2009;64:1049–1057.
    1. Leng S, Chaves P, Koenig K, Walston J. Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc. 2002;50:1268–1271.
    1. Leng S, Fried LP. Inflammatory markers and frailty. In: Fulop T, Franceschi C, Hirokawa K, Pawelec G, editors. Handbook on Immunosenescence: Basic Understanding and Clinical Applications. New York: Springer; 2009. pp. 1293–1303.
    1. Yao X, Li H, Leng SX. Inflammation and immune system alterations in frailty. Clin Geriatr Med. 2011;27:79–87.
    1. Li HF, Manwani B, Leng S. Frailty, inflammation, and immunity. Aging Dis. 2001;2:466–473.
    1. Leng S, Yang H, Walston J. Decreased cell proliferation and altered cytokine production in frail older adults. Aging Clin Exp Res. 2004;16:249–252.
    1. Walston J, Fedarko N, Yang H, et al. The physical and biological characterization of a frail mouse model. J Gerontol A Biol Sci Med Sci. 2008;63:391–398.
    1. Leng SX, Xue QL, Tian J, Walston JD, Fried LP. Inflammation and frailty in older women. J Am Geriatr Soc. 2007;55:864–871.
    1. Hubbard RE, O’Mahony MS, Savva GM, Calver BL, Woodhouse KW. Inflammation and frailty measures in older people. J Cell Mol Med. 2009;13:3103–3109.
    1. Collerton J, Martin-Ruiz C, Davies K, et al. Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study. Mech Ageing Dev. 2012;133:456–466.
    1. Walston J, McBurnie MA, Newman A, et al. Frailty and activation of the inflammation and coagulation systems with and without clinical morbidities: results from the Cardiovascular Health Study. Arch Intern Med. 2002;162:2333–2341.
    1. Leng SX, Tian X, Matteini A, et al. IL-6-independent association of elevated serum neopterin levels with prevalent frailty in community-dwelling older adults. Age Ageing. 2011;40:475–481.
    1. Ramarathan R, Kohli A, Ingaramo MC, et al. Serum chitotriosidase, a putative marker of chronically activated macrophages, increases with normal aging. J Gerontol A Biol Sci Med Sci. 2013;68:1303–1309.
    1. Leng SX, Xue QL, Tian J, Huang Y, Yeh SH, Fried LP. Association of neutrophil and monocyte counts with frailty in community-dwelling older women: results from the Women’s Health and Aging Studies I. Exp Gerontol. 2009;44:511–516.
    1. Semba RD, Margolick JB, Leng S, Walston J, Ricks MO, Fried LP. T cell subsets and mortality in older community-dwelling women. Exp Gerontol. 2005;40:81–87.
    1. De FU, Wang GC, Fedarko NS, Walston JD, Casolaro V, Leng SX. T-lymphocytes expressing CC chemokine receptor-5 are increased in frail older adults. J Am Geriatr Soc. 2008;56:904–908.
    1. Loetscher P, Uguccioni M, Bordoli L, et al. CCR5 is characteristic of Th1 lymphocytes. Nature. 1998;391:344–345.
    1. Qu T, Yang H, Walston JD, Fedarko NS, Leng SX. Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty. Cytokine. 2009;46:319–324.
    1. Qu T, Walston JD, Yang H, et al. Upregulated ex vivo expression of stress-responsive inflammatory pathway genes by LPS-challenged CD14(+) monocytes in frail older adults. Mech Ageing Dev. 2009;130:161–166.
    1. Schmaltz HN, Fried LP, Xue QL, Walston J, Leng SX, Semba RD. Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women. J Am Geriatr Soc. 2005;53:747–754.
    1. Wang GC, Kao WH, Murakami P, et al. Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study. Am J Epidemiol. 2010;171:1144–1152.
    1. Leng SX, Qu T, Semba RD, et al. Relationship between cytomegalovirus (CMV) IgG serology, detectable CMV DNA in peripheral monocytes, and CMV pp65(495–503)-specific CD8(+) T cells in older adults. Age (Dordr) 2011;33:607–614.
    1. Leng SX, Li H, Xue QL, et al. Association of detectable cytomegalovirus (CMV) DNA in monocytes rather than positive CMV IgG serology with elevated neopterin levels in community-dwelling older adults. Exp Gerontol. 2011;46:679–684.
    1. Visser M, Pahor M, Taaffe DR, et al. Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. J Gerontol A Biol Sci Med Sci. 2002;57:M326–M332.
    1. Ferrucci L, Penninx BW, Volpato S, et al. Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels. J Am Geriatr Soc. 2002;50:1947–1954.
    1. Puts MT, Visser M, Twisk JW, Deeg DJ, Lips P. Endocrine and inflammatory markers as predictors of frailty. Clin Endocrinol (Oxf) 2005;63:403–411.
    1. Chaves PH, Semba RD, Leng SX, et al. Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women’s Health and Aging Studies I and II. J Gerontol A Biol Sci Med Sci. 2005;60:729–735.
    1. Newman AB, Gottdiener JS, Mcburnie MA, et al. Associations of subclinical cardiovascular disease with frailty. J Gerontol A Biol Sci Med Sci. 2001;56:M158–M166.
    1. Leng SX, Cappola AR, Andersen RE, et al. Serum levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone sulfate (DHEA-S), and their relationships with serum interleukin-6, in the geriatric syndrome of frailty. Aging Clin Exp Res. 2004;16:153–157.
    1. Leng SX, Hung W, Cappola AR, Yu Q, Xue QL, Fried LP. White blood cell counts, insulin-like growth factor-1 levels, and frailty in community-dwelling older women. J Gerontol A Biol Sci Med Sci. 2009;64:499–502.
    1. Michelon E, Blaum C, Semba RD, Xue QL, Ricks MO, Fried LP. Vitamin and carotenoid status in older women: associations with the frailty syndrome. J Gerontol A Biol Sci Med Sci. 2006;61:600–607.
    1. Vasto S, Mocchegiani E, Malavolta M, et al. Zinc and inflammatory/immune response in aging. Ann N Y Acad Sci. 2007;1100:111–122.
    1. Arai Y, Takayama M, Gondo Y, et al. Adipose endocrine function, insulin-like growth factor-1 axis, and exceptional survival beyond 100 years of age. J Gerontol A Biol Sci Med Sci. 2008;63:1209–1218.
    1. Reiner AP, Aragaki AK, Gray SL, et al. Inflammation and thrombosis biomarkers and incident frailty in postmenopausal women. Am J Med. 2009;122:947–954.
    1. LaCroix AZ, Gray SL, Aragaki A, et al. Statin use and incident frailty in women aged 65 years or older: prospective findings from the Women’s Health Initiative Observational Study. J Gerontol A Biol Sci Med Sci. 2008;63:369–375.
    1. Liu LK, Lee WJ, Liu CL, et al. Age-related skeletal muscle mass loss and physical performance in Taiwan: implications to diagnostic strategy of sarcopenia in Asia. Geriatr Gerontol Int. 2013;13:964–971.
    1. Rockwood K, Bergman H. FRAILTY: a report from the 3(rd) Joint Workshop of IAGG/WHO/SFGG, Athens, Jan 2012. Can Geriatr J. 2012;15:31–36.
    1. Sternberg SA, Levin R, Dkaidek S, Edelman S, Resnick T, Menczel J. Frailty and osteoporosis in older women – a prospective study. Osteoporos Int. 2013 Sep 4; Epub.
    1. Varadhan R, Walston J, Cappola AR, Carlson MC, Wand GS, Fried LP. Higher levels and blunted diurnal variation of cortisol in frail older women. J Gerontol A Biol Sci Med Sci. 2008;63:190–195.
    1. Shardell M, Hicks GE, Miller RR, et al. Association of low vitamin D levels with the frailty syndrome in men and women. J Gerontol A Biol Sci Med Sci. 2009;64:69–75.
    1. Blaum CS, Xue QL, Michelon E, Semba RD, Fried LP. The association between obesity and the frailty syndrome in older women: the Women’s Health and Aging Studies. J Am Geriatr Soc. 2005;53:927–934.
    1. Woods NF, LaCroix AZ, Gray SL, et al. Frailty: emergence and consequences in women aged 65 and older in the Women’s Health Initiative Observational Study. J Am Geriatr Soc. 2005;53:1321–1330.
    1. Hubbard RE, Lang IA, Llewellyn DJ, Rockwood K. Frailty, body mass index, and abdominal obesity in older people. J Gerontol A Biol Sci Med Sci. 2010;65:377–381.
    1. Strandberg TE, Sirola J, Pitkala KH, Tilvis RS, Strandberg AY, Stenholm S. Association of midlife obesity and cardiovascular risk with old age frailty: a 26-year follow-up of initially healthy men. Int J Obes (Lond) 2012;36:1153–1157.
    1. Stenholm S, Guralnik JM, Bandinelli S, Ferrucci L. The prognostic value of repeated measures of lower extremity performance: should we measure more than once? J Gerontol A Biol Sci Med Sci. 2013 Nov 23; Epub.
    1. Strandberg TE, Pitkala KH. Frailty in elderly people. Lancet. 2007;369:1328–1329.
    1. Makary MA, Segev DL, Pronovost PJ, et al. Frailty as a predictor of surgical outcomes in older patients. J Am Coll Surg. 2010;210:901–908.
    1. Ronning B, Wyller TB, Seljeflot I, et al. Frailty measures, inflammatory biomarkers and post-operative complications in older surgical patients. Age Ageing. 2010;39:758–761.
    1. Afilalo J, Karunananthan S, Eisenberg MJ, Alexander KP, Bergman H. Role of frailty in patients with cardiovascular disease. Am J Cardiol. 2009;103:1616–1621.
    1. Iqbal J, Denvir M, Gunn J. Frailty assessment in elderly people. Lancet. 2013;381:1985–1986.
    1. Yao X, Hamilton RG, Weng NP, et al. Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults. Vaccine. 2011;29:5015–5021.
    1. Ridda I, MacIntyre CR, Lindley R, et al. Immunological responses to pneumococcal vaccine in frail older people. Vaccine. 2009;27:1628–1636.
    1. Hamaker ME, Jonker JM, de Rooij SE, Vos AG, Smorenburg CH, van Munster BC. Frailty screening methods for predicting outcome of a comprehensive geriatric assessment in elderly patients with cancer: a systematic review. Lancet Oncol. 2012;13:e437–e444.
    1. Audisio RA, van LB. When reporting on older patients with cancer, frailty information is needed. Ann Surg Oncol. 2011;18:4–5.
    1. Extermann M, Overcash J, Lyman GH, Parr J, Balducci L. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol. 1998;16:1582–1587.
    1. Courtney-Brooks M, Tellawi AR, Scalici J, et al. Frailty: an outcome predictor for elderly gynecologic oncology patients. Gynecol Oncol. 2012;126:20–24.
    1. Aaldriks AA, van der Geest LG, Giltay EJ, et al. Frailty and malnutrition predictive of mortality risk in older patients with advanced colorectal cancer receiving chemotherapy. J Geriatr Oncol. 2013;4:218–226.
    1. Bennett JA, Winters-Stone KM, Dobek J, Nail LM. Frailty in older breast cancer survivors: age, prevalence, and associated factors. Oncol Nurs Forum. 2013;40:E126–E134.
    1. Desquilbet L, Jacobson LP, Fried LP, et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J Gerontol A Biol Sci Med Sci. 2007;62:1279–1286.
    1. Desquilbet L, Margolick JB, Fried LP, et al. Relationship between a frailty-related phenotype and progressive deterioration of the immune system in HIV-infected men. J Acquir Immune Defic Syndr. 2009;50:299–306.
    1. Piggott DA, Muzaale AD, Mehta SH, et al. Frailty, HIV infection, and mortality in an aging cohort of injection drug users. PLoS One. 2013;8:e54910.
    1. Boyle PA, Buchman AS, Wilson RS, Leurgans SE, Bennett DA. Physical frailty is associated with incident mild cognitive impairment in community-based older persons. J Am Geriatr Soc. 2010;58:248–255.
    1. Buchman AS, Boyle PA, Wilson RS, Tang Y, Bennett DA. Frailty is associated with incident Alzheimer’s disease and cognitive decline in the elderly. Psychosom Med. 2007;69:483–489.
    1. Song X, Mitnitski A, Rockwood K. Nontraditional risk factors combine to predict Alzheimer disease and dementia. Neurology. 2011;77:227–234.
    1. Theou O, Stathokostas L, Roland KP, et al. The effectiveness of exercise interventions for the management of frailty: a systematic review. J Aging Res. 2011;2011:569194.
    1. Gill TM, Baker DI, Gottschalk M, Peduzzi PN, Allore H, Byers A. A program to prevent functional decline in physically frail, elderly persons who live at home. N Engl J Med. 2002;347:1068–1074.
    1. Fiatarone MA, O’Neill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med. 1994;330:1769–1775.
    1. Forster A, Lambley R, Hardy J, et al. Rehabilitation for older people in long-term care. Cochrane Database Syst Rev. 2009;(1):CD004294.
    1. Clegg AP, Barber SE, Young JB, Forster A, Lliffe SJ. Do home-based exercise interventions improve outcomes for frail older people? Findings from a systemic review. Rev Clin Gerontol. 2012;22:68–78.
    1. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363:109–122.
    1. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–333.
    1. Friedlander AL, Butterfield GE, Moynihan S, et al. One year of insulin-like growth factor I treatment does not affect bone density, body composition, or psychological measures in postmenopausal women. J Clin Endocrinol Metab. 2001;86:1496–1503.
    1. Campbell S, Szoeke C. Pharmacological treatment of frailty in the elderly. J Pharm Pract Res. 2009;39:147–151.

Source: PubMed

3
Abonner